Immunology is quite a fringe speciality in clinical medicine, and many people, even doctors, are not sure what a clinical immunologist is or does. Indeed, the role itself can be quite variable.
Through laboratory work, we are involved in the diagnosis and monitoring of a broad range of clinical conditions across all of medicine. In clinical practice, virtually all immunologists see patients with inborn errors of immunity (mainly immunodeficiency), secondary immunodeficiency and specialist allergy. Beyond this there are many local arrangements for sole or joint care of other patients with immune-mediated conditions.
The 1940–60s is often described as the heyday of British immunology. During this time there was an outpouring of research laying the foundations of our current understanding of immunoglobulins, cellular immunity and complement function. The practice of clinical immunology arose from scientifically trained doctors who shared a fascination in the role of the immune system in disease. They drew on – and often led – the rapid advances in the understanding of the immune system in the 20th century. In this article, Dr Aarnoud Huissoon, Consultant Immunologist at University Hospitals Birmingham NHS Foundation Trust, explores the early history of clinical immunology.
Three men in a punt
In the 1930s, John Humphrey, John Squire and Philip Gell studied natural sciences together in Cambridge, before they went on to their clinical training at University College Hospital. These three scientists went on to become vital figures in the development of immunology.
Humphrey gravitated to immunology at an early stage in its clinical development. He led the Division of Immunology at the Medical Research Council's National Institute of Health Research (NIHR) in London. From there he mentored and advised many of the physicians who became the first wave of clinical immunologists. Among these was Geoffrey Asherson, a clinical researcher whose work included demonstration of tolerising doses of antigen and suppressor T cells. In 1971, David Webster, a young senior registrar, joined the NIHR and became one of the first trainees specifically appointed to the emerging specialty of immunology. Webster went on to lead the immunodeficiency research group and diagnosed and managed immunodeficiency at Northwick Park and later at the Royal Free Hospital.
Meanwhile, John Squire – physician, dermatologist and pathologist – was asked by the MRC to undertake research into the causes and treatment of occupational skin disorders in England's industrial heartland, Birmingham. Not content with such a modest brief, he quickly established a reputation as a multi-specialty busybody and was appointed by the University of Birmingham to set up their new Department of Experimental Pathology. He invited his friend Philip Gell to join him there, and the foundations of clinical immunology were in place.
Philip Gell's research after the war focused on contact dermatitis caused by chemicals in explosives. This led him to an interest in delayed hypersensitivity, later known to be cell-mediated immunity. As time went on, his interests widened, and his department in Birmingham produced world-leading research into how antigen recognition by antibodies and T cells differed, and evidence that B cells could be stimulated through immunoglobulins acting as receptors on the cell surface.
The first textbook of clinical immunology…
Together with Cambridge haematologist, Robin Coombs, Gell described four types of aberrant immune responses (or ‘allergies’ as they termed them), coining the Gell and Coombs classification of hypersensitivity that is still widely taught today. In 1963 they published what was probably the first and certainly the most influential book to underpin what would become a new specialty: Clinical Aspects of Immunology. This text brought together the current understanding of immune mechanisms of disease, including immunity to infectious disease, autoimmunity and atopic allergy. For the first time, protocols for immunology laboratory diagnostic methods sat alongside descriptions of disease pathogenesis and treatment.
…and the first NHS immunologist
In London around this time, junior doctor, Ronald Thompson, became interested in immunology through recent discoveries in autoimmunity, and wrote a paper on rheumatoid factor in patients who had suffered heart attacks. He was advised by John Humphrey that he might develop his interest by working with Philip Gell in Birmingham. He soon started work in the department, learning the techniques for autoantibody testing and complement measurement.
While Thompson was learning his trade, five miles away in East Birmingham Hospital virologist, Tim Flewett, was struggling with requests for immunological advice. Squire and other clinical researchers at the university were also physicians at this general hospital which specialised in infectious diseases. Flewett persuaded the local health board to create a post for a specialist in immunology, and in 1969, Ron Thompson was appointed as the first immunologist in the NHS.
Starting with only a technician and a secretary, Thompson went on to create the model of clinical immunology practice that is still recognisable today. He was the first to bring the immunology diagnostic repertoire together into one laboratory, where previously individual research departments would provide a few tests according to their own interests and expertise. He reviewed patients with recurrent or unusual infections alongside well-known infectious diseases expert, Alastair Geddes, and immunoglobulin and other emerging immunological therapies were prescribed from his clinic.
Measuring the immune system
As time went on, new techniques such as gel precipitation, electrophoresis and immunofluorescence enabling measurement and quantitation of autoantibodies were developed, and the clinical relevance of the immune system uncovered. In Cambridge, Robin Coombs showed that haemolytic anaemia was caused by an autoantibody, which could also cause haemolysis in vitro. Jack Pepys in London used immunoprecipitation to show that certain lung diseases were associated with antibodies to fungal proteins and other organic dusts. Deborah Doniach and Ivan Roitt demonstrated the first tissue-specific autoantibodies (thyroid and parietal cell) using immunofluorescence. John Holborrow and Gerald Johnson then used this technique to show autoantibodies against smooth muscle in liver disease and also antinuclear antibodies, which could be used to diagnose systemic lupus erythematosus (SLE) (in place of the more laborious LE test).
Clinical demand for these tests followed and these were initially performed alongside other biochemistry, haematology and microbiology analyses. Immunology laboratories emerged often where there was an associated university department where the required technical expertise existed to perform these increasingly specialised manual tests.
As more laboratories introduced immunology tests, there was inevitably wide variation in the quality of the results. For immunoglobulins and some other proteins, the WHO in Lausanne (headed by David Rowe, from Squire's laboratory in Birmingham) had developed standards. For many years the Protein Reference Unit (laboratories in London, Sheffield, Birmingham and Cardiff) provided the reference standard for immunochemistry and related assays. But for many other subjective and interpretative tests, no standards were available. The introduction of external quality control was an important step to ensure that test results for antinuclear or gliadin antibodies, for example, gave similar results no matter where they were tested. NEQAS (National External Quality Assessment Service) for immunology began in the 1980s. Blood samples were sent to all participating laboratories and the collated results were circulated so that each laboratory could compare its performance to others. Outliers were encouraged to re-examine their practices to identify causes for this. Clinical Pathology Accreditation Ltd was formed in 1992 by a number of UK pathology organisations to ensure consistency in laboratory practice. These exemplars of good clinical practice have been adopted widely across the globe.
Clinical immunology professional Societies – from BSI and back again
In 1956, Humphrey, along with other prominent immunologists, founded the British Society for Immunology. Eight years earlier, in 1948, Frankland set up the British Allergy Society, the forerunner of the BSACI. While there were clear overlaps with the interests of these two Societies, there was a need to represent the activities of the growing clinical immunology community. And so Gavin Spickett became the first chair of the UK Primary Immunodeficiency Network (UKPIN), which held its inaugural meeting at East Birmingham Hospital in 2000.
UKPIN went on to hold bi-annual meetings and, importantly, developed a set of standards against which centres managing immunodeficiency patients could self-assess their performance and facilities, and apply for peer accreditation. Keen to recapture the clinical fraternity, the BSI also set up a clinical immunology subgroup, which organised clinical content at the annual BSI Congress. But immunologists found themselves stretched between many different relatively small representative organisations, each with its own officers and meetings. Thus, in 2023, the formal merger of UKPIN into the BSI occurred, to form the BSI Clinical Immunology Professional Network (BSI-CIPN). Like UKPIN before it, this intended to cater not only for medically qualified immunologists, but also the nursing and scientific members of our departments. So, from John Humphrey’s original founding intentions for the society, clinical immunology has come home again.